| Intracerebral infection of Theiler's virus induces an immune-mediated demyleinating disease in susceptible mice, such as SJL mice, providing an excellent infection-induced animal model of human multiple sclerosis. In contrast, B6 mice are resistant to infection mainly due to strong virus-specific CD8+ T cell responses in the CNS. For this reason, T cell immune responses in B6 mice have been often compared to those in susceptible SJL mice to understand the nature of protective vs. pathogenic immunity. Therefore, first two chapters in this thesis, aimed to investigate and compare Vbeta repertoire of antigen-specific CD8+ T cells in resistant vs. susceptible mice. In the last chapter, we aimed to investigate CD4+ T cell responses since functional repertoire maturation of virus-specific CD4+ T cells during the TMEV infection is not studied well so far although oilgo-clonal expansion of virus-specific CD4+ T cells involved in disease progression of susceptible SJL mice. Hence, we developed TCR transgenic mice to investigate the functional status and the role of virus-specific CD4+ T cells in the CNS. We found that most of antigen-specific CD4+ T cells are predisposed to an antigen-unresponsive state in the CNS. However, the disease onset and progression of 69Tg (TCR transgenic mice in susceptible genetic background) mice were accelerated compared to those of 69B6.S (TCR transgenic mice in resistant genetic background) mice. Since these results are tightly correlated with higher number of Th17 cell infiltration in the CNS, Th17 cells may play an important role in the pathogenesis of susceptible mice.;In summary, from the data presented in this thesis, we hypothesize that strong CD8+ T cell responses do not necessarily have to be a result of broad spectrum of Vbeta family. In addition, although very few CD4+ T cells produce inflammatory cytokines like IL-17 and IFN-gamma, CD4+ T cells seem to be the key players in this disease model since they are sufficient to cause progressive demyelinating disease in the CNS. Therefore, this thesis gives important insights into to the CNS infiltrating virus-specific CD8+ and CD4+ T cell repertoire. |
